The pancreas comprises two glandular tissues, one, is a collection of cells that form the exocrine function of the pancreas where these exocrine cells synthesize and release digestive enzymes into the intestine; the second tissue comprises the endocrine function of the pancreas which synthesize and release hormones into the circulation. Of prime importance in the endocrine function of the pancreas, are the xcex2-cells. These cells synthesize and secrete the hormone insulin. The hormone insulin plays a vital role in maintaining normal physiological glycemic levels. There are molecules that are effectors of the endocrine cells of the pancreas. Incretins are an example of such molecules. Incretins potentiate glucose-induced insulin secretion from the pancreas.
Incretins such as glucagon-like peptide-1 (7-36) amide (xe2x80x9cGLP-1xe2x80x9d; or the lizard analog Exendin-4) and gastric inhibitory polypeptide (xe2x80x9cGIPxe2x80x9d) have been demonstrated to be insulinotropic, i.e., their presence or stabilization can maintain acute glycemic control by their insulin-secretive effects (Demuth, H. U., et al., DE 196 16 486:1-6, 1996; Pauly, R. P. et al., Regul. Pept. 64 (1-3): 148, 1996, the teachings of which are incorporated herein by reference in their entirety). Additionally, it has been demonstrated that GLP-1 acts, as an islet growth hormone by stimulating xcex2-cell proliferation, cell mass increase and by promoting undifferentiated pancreatic cells in specialized cells of the islet of Langerhans. Such cells show improved secretion of insulin and glucagon (Yaekura, K. et al., IN: VIP, PACAP, and Related Peptides, W. G. Forssmann and S. I. Said (eds.), New York: New York Academy of Sciences, 1998, p. 445-450; Buteau, J. et al., Diabetologia 42(7): 856-864, 1999, the entire teachings of which are herein incorporated by reference).
It has been previously proposed to apply exogenous bioactive GLP-1, or its analogs, to either stimulate islet cell regeneration in vivo, or to obtain pancreatic cells from diabetes mellitus patients and to treat such cells ex vivo in tissue culture using bioactive GLP-1. This ex vivo treatment was considered to facilitate regeneration and/or differentiation of islet cells which could then synthesis and secrete insulin or glucagon (Zhou, J. et al., Diabetes, 48(12):2358-2366, 1999; Xu, G. et al., Diabetes, 48(12):2270-2276, 1999, the entire teachings of which are herein incorporated by reference).
However, such a treatment regime requires the enteral or parenteral application of bioactive GLP-1 to patients, including the possibility of surgery. It is one aspect to obviate the need for surgical treatment, enteral or parenteral applications of bioactive GLP-1.
The present invention relates to a novel method in which the reduction of activity in the enzyme Dipeptidyl Peptidase (DP IV or CD 26) or of DP IV- like enzyme activity in the blood of mammals induced by effectors of the enzyme leads as a causal consequence to a reduced degradation of the gastrointestinal polypeptide Glucagon-Like Peptide Amide-1 7-36 (GLP-17-36) (or structurally related functional analogs of this peptide, such as GLP-17-37, or truncated but biologically active fragments of GLP-17-36) by DP IV and DP IV-like enzymes. Such treatment will result in a reduction or delay in the decrease of the concentration of functional active GLP-1 (including GLP-1 -derived) circulating peptide hormones or of their analogs.
As a consequence of the resulting enhanced stability of the endogenous GLP-1 (including GLP-1 -derived) circulating peptides caused by the inhibition of DP IV activity, GLP-1 activity is prolonged resulting in functionally active GLP-1 (including GLP-1-derived) circulating peptide hormones facilitating growth-hormone-like stimulation of pancreatic cells in such a way that these cells proliferate to functionally active cells of the Islets of Langerhans. Additionally, insensitive pancreatic cells or impaired pancreatic cells may be transformed into functionally active cells of the islets of Langerhans when exposed to GLP-1.
It was expected, that the transformation of insensitive pancreatic cells or impaired pancreatic cells to functionally active cells of the islets of Langerhans results in an increased insulin secretion and in an increased insulin level in blood plasma. Surprisingly, in studies in healthy human volunteers and obese, diabetic Zucker rats, the insulin level decreased after treatment with the DP IV inhibitor isoleucyl thiazolidine hemifumarate (P32/98) (see examples 1 and 2, respectively). Nevertheless, the resulting regeneration of the islets of Langerhans does change the efficacy of endogenous insulin and other islet hormones, such as glucagon, in such a way that stimulation of carbohydrate metabolism of a treated mammal is effected. As a result, the blood glucose level drops below the glucose concentration characteristic for hyperglycemia, as shown in examples 1 and 2. The mechanism triggering these effects is not known in detail. However, this resulting regeneration of the islet cells further effects anomalies of the metabolism including glucosuria, hyperlipidaemia as well as severe metabolic acidoses and Diabetes mellitus, by preventing or alleviating these sequela.
In contrast to other proposed methods known in the art, such as pancreatic cell or tissue transplantation or ex-vivo treatment of pancreatic cells using GLP- 1 or exendin-4 followed by re-implantation of the treated cells, the present invention does not cause or require complicated and costly surgery, and provides an orally available therapy. The instant invention represents a novel approach for lowering the elevated concentration of blood glucose. It is commercially useful and suitable for use in a therapeutic regime, especially concerning human disease, many of which are caused by prolonged elevated or blood glucose levels.